No abstract

The effect of aging on the distribution and elimination of ethanol was studied in a group of 50 healthy subjects ranging in age from 21 to 81 yr (mean, 53.3). Ethanol was administered in a continuous 1-hr infusion at a mean rate of 375 mg/m2 body surface area/min (equivalent to a mean dose of 0.57 gm/kg body weight). Serial blood samples for the determination of ethanol concentration was obtained at 15- to 30-min intervals for up to 4 hr post infusion. Ethanol elimination and distribution were evaluated with the aid of a two-compartment model. Rates of ethanol elimination were not affected by age. Peak ethanol concentration in blood water at the end of the infusion period was correlated with age (r= 0.55, p less than 0.001). Lean body mass and total volume of distirbution fo the ethanol were negatively correlated with age. The smaller volume of distirbution, in association with the decreased lean body mass, most likely explains the higher peak ethanol concentration found in the blood after administration of an ethanol does on the basis of surface area in the old as compared with the young subjects. This study demonstrates that age-related changes in body composition are important factors in the study of ethanol metabolism and its pharmacologic effects.

The product of the scl (also called tal‐1 or TCL5) gene is a basic domain, helix–loop–helix (bHLH) transcription factor required for the development of hematopoietic cells. Additionally, scl gene disruption and dysregulation, by either chromosomal translocations or a site‐specific interstitial deletion whereby 5′ regulatory elements of the sil gene become juxtaposed to the body of the scl gene, is associated with T‐cell acute lymphoblastic leukemia (ALL) and T‐cell lymphoblastic lymphoma. Here we show that an inappropriately expressed scl protein, driven by sil regulatory elements, can cause aggressive T‐cell malignancies in collaboration with a misexpressed LMO1 protein, thus recapitulating the situation seen in a subset of human T–cell ALL. Moreover, we show that inappropriately expressed scl can interfere with the development of other tissues derived from mesoderm. Lastly, we show that an scl construct lacking the scl transactivation domain collaborates with misexpressed LMO1, demonstrating that the scl transactivation domain is dispensable for oncogenesis, and supporting the hypothesis that the scl gene product exerts its oncogenic action through a dominant‐negative mechanism.

Interchromosomal translocations within lymphoid neoplasms frequently involve the antigen receptor genes. We cloned the breakpoints of the t(l1;14)(p15;q11) in a CD3-negative T-cell acute lymphoblastic leukemia cell line (RPMI 8402) in order to identify new genes potentially involved in T-cell neoplasia. An extensive comparison of both breakpoints and their germ line counterparts indicated that an inadvertant recombinasemediated break at chromosome segment llplS recombined with the 6 T-cell receptor at 14qll. The derivative 11 breakpoint resembles a coding joint in which llplS rather than a variable region was introduced 5' to a D81D82J81 intermediate rearrangement. Conversely, the derivative 14 breakpoint corresponds to a signal joint between the 5' heptamer-spacer-nonamer recombinational signal of Dr, and an isolated heptamer at llplS.Multiple, apparently distinct transcripts were found flanking both breakpoints of 8402. RNAs of 3.5, 4.4, 1.4, and 8.0 kilobases originating from either side of the derivative 14 breakpoint were highly expressed in 8402 compared with other cells. This suggests that this translocation deregulated multiple genes and provides the opportunity to assess any multifactorial contribution they may have to malignancy. We cloned and sequenced several cDNAs representing the 1.4-kilobase transcript (termed Ttg-1 [T-cell translocation gene 1]) from an 8402 library. The predicted protein of 156 amino acids contained two internal repeats which could potentially form zinc fingers.Chromosomal translocations are frequently found in malignant cells but not in their normal cellular counterparts. Moreover, unique translocations are associated with histologically and phenotypically distinct neoplasms (43,56, 57). Lymphoid malignancies often possess translocations at the chromosomal sites of the antigen receptor genes, immunoglobulin genes in B-cell neoplasms, or T-cell receptor (TCR) genes in T-cell neoplasms (for a review, see reference 31). These genes normally rearrange during development to assemble separate variable (V), joining (J), and, at times, diversity (D) segments into a contiguous V(D)J coding joint. A site-specific recombinase cleaves at conserved heptamerspacer-nonamer signal sequences, which flank the coding regions of these gene segments (33,53), removing the intervening DNA segments and ligating the signal sequences to each other to generate extrachromosomal circles (22,41). These genes prove to be the most frequent sites for illegitimate recombinations with nonhomologous chromosomes in lymphoid neoplasms (31).Genes located at the sites of such translocations appear to directly participate in the development or maintenance of the malignant phenotype (29). Interchromosomal translocations can deregulate these candidate oncogenes by a variety of mechanisms. Transcriptional activation due to the introduction of enhancer elements has been shown for c-myc in a transgenic mouse model (1). Disruption of normal transcription by acquired somatic mutation has been noted for c-myc in the t(8;14)(q...